JP2017516831A - Formulation containing silicone oil for nasal application - Google Patents

Abstract

The present invention is intended for use in nasal treatments of nasal diseases caused by intrinsic and / or exogenous causes, such as diseases of the type caused by bacteria, fungi, viruses and / or allergens. The present invention relates to a silicone oil-containing preparation for nasal application. According to the present invention, the silicone oil or the formulation is, if desired, preferably in the presence of an emulsifier and optionally an additional active ingredient such as an α-sympathomimetic agent, for example oxymetazoline or xylometazoline. Enriched with oxygen in the presence. The invention also relates to related subject matter according to the invention.

Description

  The present invention relates to a silicone oil for nasal application in an intranasal treatment of nasal diseases, particularly rhinitis, due to intrinsic nasal diseases and / or exogenous causes such as bacteria, fungi, viruses and / or allergens. It relates to a preparation containing.

  Inflammatory diseases of the nasal mucosa are one of the most common reasons for illness and affect millions of people of all ages every year in Germany. Older people and people with immune deficiencies exhibit particularly severe disease symptoms, which are characterized by swelling with dyspnea and complications and edema formation of the nasal mucosa. Complications of concern include inflammation of the paranasal mucosa due to edematous mucosal swelling around the opening of the airspace located in the nasal cavity, which then no longer allows pressure equalization and suppuration. It gets worse enough to cause The most common cause is rhinovirus or other viral vectors in the cold season, but influenza viruses may also use nasal mucosal cells as the site of viral outbreaks, and to typical stimulation and secretion Lead. Apart from viral etiology, bacterial species also grow in the nasal mucosa, especially in people with immunodeficiency, which often leads to chronic nasal inflammation (odorous rhinosis), and Difficult to treat. Further common causes of nasal mucosal irritation are allergens such as flower pollen, animal epithelial components and other organic dust, which induce an immune response in the nasal and upper respiratory mucosa . As a result, severe swelling and irritation are seen simultaneously with liquid nasal secretions. Although this form of rhinitis is not infectious, as observed, in contrast to the viral and bacterial rhinitis forms described above, those affected by the disease have more common symptoms such as headache, general Fatigue and fatigue. Rhinitis disease is a typical seasonal widespread disease that rarely has a severe course, but with high economic impact. Thus, various forms of rhinitis: allergic rhinitis (Rhinitis allergica), viruses, bacteria or fungi (general sensibility) rhinitis, eg acute rhinitis (Rhinitis acuta) and even atrophy Rhinitis atrophicans (odorous rhinitis), dry rhinitis, hypertrophic rhinitis (Rhinitis hypertrophica), vasomotor rhinitis, Rhinitis pseudomembranacea, drug-induced Rhinitis medicamentosa, or chronic rhinitis, or two or more of these are known. Similarly, the disease corresponds, as a preferred or specific variant, to the term “nasal disease” or “nasal disease” mentioned above and in the following definition of the invention.

  For the repair of the nasal physiological function, various local therapeutic principles are applied: an aqueous solution or nasal ointment as a carrier of the active ingredient is intended to regenerate and wet the mucous membrane . As a result, the function of the ciliated epithelium should be maintained, and the nose becomes available again as a respiratory organ. In acute rhinitis, active ingredient-containing nasal drops, nasal sprays and salt solutions are used that restore nasal openness for some time. Basically, α-mimetics are used, which constrict the precapillaries of the nasal microcirculatory system, thus reducing fluid production. However, viral inhibitors and less common antibiotics are also used. Nasal oils, often in combination with inflammation-inhibiting plant-based active ingredients, are intended to often reduce mass and gas movement on the nasal mucosal surface and to create a protective film on the epithelium. In the presence of large amounts of secretions, these films cannot produce the desired therapeutic effect. Here, rhinitis drugs containing vasoconstrictors are advantageous, but due to their short duration of action, these locally acting drugs are introduced into the nose more frequently than necessary. . In routine use, the permanently impaired microcirculatory system leads to capillary failure and microcapillary bleeding due to congestion and microthrombosis. However, mucosal atrophy and permanent nasal dryness also result in routine use of nasal medications (drug-induced rhinitis). There is a broad market for rhinitis drugs used in various types of colds, because of its variable etiology, no causal treatment or prevention is currently possible caused by.

It is known that oxygen-containing silicone oil emulsions can be used for the treatment of gastrointestinal diseases, as described in EP 2 151 242 A1. A similar composition with no oxygen content was also described by Katja Presselt, “Preparation and characterization of silicone oil emulsions.” Preparation and characterization of silicone oil emulsions and their therapeutic potential in chronic inflammatory skin diseases. and research on their therapeutic potential in chronic inflammatory skin diseases): Biologisch-Pharmazeutische Fakultat der Friedrich-Schiller-Universitat Jena, 2010.
Recently, unexpectedly, emulsions of silicone oil in an aqueous base (especially oxygen-enriched) are suitable for the treatment of nasal diseases, even in the absence of other active ingredients Was found.

The main responsibility for this is the creep capacity of the oil emulsion, which migrates completely below the nasal cell mucus deposit due to its surface tension reducing effect in aqueous solutions. And can be separated from the substrate. Particularly suitable for this is a water-in-oil emulsion of silicone oil, as will be explained in more detail below. The therapeutic effect of dimethicone macromolecules is probably due to interaction by hydrophobic binding with the protein-sugar structure of paracellular TJ, which is destroyed and open. Suppression of microlesions caused by dimethicone quickly leads to normalization of another excessive immune response and does not reduce or attenuate it. Simultaneous supply of elemental oxygen to the mucosal surface can contribute to a further enhanced anti-infection effect. Furthermore, nasally, active ingredients are likewise incorporated into the dimethicone emulsion, which can result in additive or cumulative anti-rhinitis effects. As a result, a completely new anti-rhinitis principle and system is available, which does not show any side effects, is not absorbed and has a palliative or curative action that lasts 8-10 hours Can do. Furthermore, nasal sprays with this (especially oxygen-enriched) dimethicone emulsion are suitable for prophylactic use. If the nasal / pharyngeal mucosa is wetted by this monopreparation oxygen-dimethicone spray, for example, before contact with rhinovirus or allergen begins, for several hours (e.g. 12 or more) High reliability prevention is guaranteed. Therefore, this preventive spray may provide self-protection to people who are also suffering from immunodeficiency or who are in close contact with the public (sales staff, nurses).
The mechanism of action described above and below should not be construed as limiting.

In the first application for such a novel nasal spray, an oxygen-containing 10% dimethicone emulsion, which does not contain oxymetazoline or xylometazoline or in particular contains it, in patients suffering from acute rhinitis. Tested. Here, the application of this combination of active ingredients has shown a significant additive curative effect, and after a single application, nasal breathing was assured within the patient, often for up to 10 hours. . After repeated application, the acute rhinitis was cured, for example after 3-4 days. This combination was particularly effective in allergic fever (hay fever). Within a few hours, affected ones are free of symptoms, and once or twice daily spray application can withstand time-limited exposure to gaseous allergens, without illness symptoms. did it. In cell experiments using pharyngeal cell lines, we were able to find an effect against bacterial permeation.
Despite extreme exposure of the nasal cavity to external toxicities such as allergens and pathogens (eg viruses and bacteria), positive effects have thus been found. Similarly, it is surprising that despite the presence of oxygen in the air, a more powerful effect can be found with oxygen-containing emulsions, not with oxygen-free emulsions. This explanation is not limiting and the effect could contribute to the masking action, which is also useful for viruses.
Therefore, only relevant to the gastrointestinal tract with lower exposure to pathogens (here the nasal cavity behaves as a kind of prefilter), against the background of the above effect in EP 2 151 242 A1 Even there was a surprising activity.

Therefore, in a first aspect, the present invention provides in particular nasal intrinsic diseases and / or exogenous causes, such as nasal diseases caused by bacteria, fungi, viruses or allergens, especially mammals, especially humans. For the intranasal treatment of the corresponding disease of the nasal mucosa in nasal use, in particular a silicone oil-containing formulation, in particular an emulsion consisting of silicone oil in an aqueous medium, wherein the silicone oil is preferably oxygenated Enriched.
A further aspect of the invention is a corresponding disease of the nasal mucosa in nasal intrinsic diseases and / or extrinsic causes, for example nasal diseases caused by bacteria, fungi, viruses or allergens, especially in mammals, especially humans In connection with the use of a silicone oil-containing formulation for nasal use, in particular an emulsion consisting of silicone oil in an aqueous medium, for the manufacture of a pharmaceutical formulation for intranasal use. The silicone oil is specially enriched with oxygen.
A further aspect of the invention is for intranasal treatment of nasal intrinsic diseases and / or extrinsic causes such as nasal diseases caused by bacteria, fungi, viruses or allergens, in particular corresponding diseases of the nasal mucosa. The present invention relates to a silicone oil-containing formulation for nasal use, particularly an emulsion of silicone oil in an aqueous medium, particularly for mammals, especially humans in need of such treatment. Nasal administration in an amount effective for the nasal disease, wherein preferably the silicone oil is specially enriched with oxygen.
The following definitions allow the above and below more general terms to be replaced with more specific terms, where in an embodiment of the invention one or more of the general terms or All can be replaced with specific terms leading to a more specific and preferred embodiment of the present invention.

Emulsions consisting of silicone oil in an aqueous medium are in particular polydialkyl- or polydiphenylsilanes, especially polydi- (C ₁ -C ₇ -alkyl)-, which are liquid at room temperature (defined here as 23 ° C.). It is an oil-in-water (O / W) emulsion of silane, particularly polydimethylsiloxane (dimethicone) which is liquid at room temperature.
Examples are the following polydimethylsiloxanes of formula I:
(H ₃ C) ₃ -Si-O [-Si (CH ₃ ) ₂ -O] _n -Si (CH ₃ ) ₃ (I)
Here (on average based on the number of molecules), n = 1 to 1,000 (the above formula serves mainly as an example), preferably n = 1 to 500.
Preferred are siloxanes with an average kinematic viscosity of 10 to 5,000 mm ² s ^{−1 at} 25 ° C. (for example M10, M50, M100, M350, M500, M1000, M2000) (according to manufacturer data). And M5000, especially M10, M50, M100, M350 and M500, above all M1000 and M2000 (GE Bayer Silicones GmbH & Co KG, Leverkusen, Germany; Munich, Germany; Munich, Germany) Wacker Chemie GmbH; Hilden, Germany, Caesar & Loretz GmbH), where the numerical values in each case are: The respective kinematic viscosities expressed in mm ² s ⁻¹ units at 25 ° C. are shown and can be measured as follows:
The viscosities of these aqueous solutions can be measured, for example, using the automatic measuring instrument AVS 3650 (Schott-Gerate GmbH, D-Hofheim, Germany), the measuring instrument CT Combined with 1450 / CK 101. Various Ubbelohde capillary viscometers are used to measure samples at 20 ° C. and 25 ° C. (Table 3-9).
Table 3-9 : Overview of Ubbelohde capillary viscometer used (capillary type, classification according to Ph. Eur., Instrument number, capillary constant)

The capillary viscometer is rinsed with ethanol prior to each measurement and then dried with compressed air. The kinematic viscosity of the sample is calculated from the measured transit time through the capillary for a defined sample volume. These measurements are evaluated using the software VPC 38. Three to five measurements are made for each sample.
Particularly preferred are dimethicones having a kinematic viscosity in the range of 100 to 10,000, in particular 500 to 5,000, for example 1,000 to 2,000 mm ² s ⁻¹ .
The content by weight of the siloxane in the emulsion used according to the invention is about 0.1-50% by weight, for example 0.5-50% by weight, for example 5-25% by weight.
In order to stabilize the emulsion, an emulsifier is required.

Possible emulsifiers are: ion generating emulsifiers (eg sodium dodecyl sulfate) or preferably non ion generating emulsifiers, eg low molecular weight non-ion generating emulsifiers or block copolymers, eg macrogol Glycerol lisinoleate, such as Cremophor ^™ EL (Caesar & Loretz GmbH, D-Hilden, Germany);
Polyoxyethylene sorbitan fatty acid esters, for example, Tween (Tween ^TM) 80 (Germany, Hilden Caesar & Rorettsu GmbH);
Mixtures of partial fatty acid esters of sorbitol and its anhydride with oleic acid, for example Span ^™ 80 (Sigma-Aldrich Chemie GmbH, D-Steinheim, Germany);
Phospholipids such as Lipoid S100 (Lipoid GmbH, D-Ludwigshafen, Germany) (phosphatidylcholine, phosphatidylethanolamine, N-acyl-phosphatidylethanolamine, phosphatidylinositol, lysophosphatidylcholine, triglyceride , A mixture containing free fatty acids and DL-α-tocopherol);
Block copolymers having ethylene oxide and propylene oxide units, for example, poloxamers (Poloxamer) 188 (e.g., Lutrol (Lutrol ^TM), Germany, BASF of Ludwigshafen (BASF), Inc.)
Hydroxypropyl methylcellulose (eg, Metrolose ^™ from Shin-Etsu Chemical Co., Ltd, J-Tokyo, Japan);
In the form of a copolymer of polydimethyl silane and organic glycols, for example, Bellshill (Belsil ^TM) (Germany, Wacker Chemie (Wacker Chemie) GmbH, Munich (D-Munich)), or a form obtained by methanol fractionation A silicone surfactant (expressed as HSY 115);
(- Kagakufuzu Corporation (Mitsubishi-Kagaku Foods Co.), Japan, Tokyo Mitsubishi of (J-Tokyo)) sucrose esters such as, dominant (predominant) as an acyl minute for example, Lyoto sugar ester (Ryoto ^TM Sugar Ester) Esters with lauric acid (L-595), esters with myristic acid (M-1695), esters with oleic acid (O-170 or O-1570), or esters with stearic acid (S-570 or S- 1570);
Or two or more mixtures of these, for example, Tween (Tween ^TM) 80 and Span (Span ^TM) 80 mixture of (mixtures expressed as HLB 8.5),
Or similarly particulate solids, such as modified silicon dioxide particles.

Particularly preferred are block copolymers having ethylene oxide and propylene oxide units, such as sucrose esters of stearic acid as poloxamer 188, or even predominant acyl component, for example S-570, Tween (Tween ^TM) 80, etc. alone polyoxyethylene sorbitan fatty acid ester, or a partial fatty acid esters of sorbitol and its anhydrides, those mixed with a mixture of oleic acid, for example, span (span ^TM) 80, macrogol glycerol ricinoleate, e.g. Cremophor ( Cremophor ^™ ) EL or phospholipid, such as Lipoid S100, or a mixture of two or more thereof.
The content by weight of the emulsifier, based on the finished emulsion, is preferably in the range from 0.01 to 20% by weight, in particular from 1 to 10% by weight.
Examples of the aqueous medium include pure water, a buffer solution (for example, a phosphate buffer solution adjusted to pH by a base such as NaOH or phosphoric acid) or other salt solution (for example, sodium chloride or potassium chloride) dissolved in water. Hypotonic, isotonic or hypertonic solutions) can also be used, or it can be seawater. The content of the aqueous medium in the whole composition is preferably 40-99.9% by weight, for example 60-99% by weight.
Further possible additives are thickeners (“quasi-emulsifiers”) such as gum arabic, tragacanth; polyalkylene glycols such as polyethylene glycol or polypropylene glycol, sugar alcohols or regulators of osmotic activity. Other substances that may serve as, for example, sorbitol, hexitol or mannitol, preservatives (especially in the presence of active ingredients and / or in the absence of oxygen), such as ethylenediaminetetraacetic acid, antioxidants such as ascorbic acid, BHA or BHT, parabens, benzoic acid, cetyltrimethylammonium chloride, sorbic acid or thiomersal; pigments or dyes such as β-carotene, erythrosin, Sunset Yellow FCF, indigotin, etc. aromatizing substances such as fruit esters Or vanillin and liquid Triol such as glycerin, is selected from propylene glycol or ethylene glycol, which is preferably a whole, 0-40 wt%, may be added in an amount of, for example, 0.1 to 10 mass%.

Oxygen (O ₂ ) binds associatively at a very high concentration in the emulsions used according to the invention compared to other gases (nitrogen, carbon dioxide), for example up to about 80 g of oxygen (kg of methylpolysiloxane ( O ₂ ) can be bound.
It is advantageous to set the particle size of the silicone oil emulsion to D99 within an average value range of 0.3 to 15 μm, for example 2 to 10 μm, or within a range of 0.5 to 200 μm, for example 5 to 50 μm. Here, the particle size is a laser using a LS 230 Particle Sizer (Small Volume Module, Beckman-Coulter GmbH, D-Krefeld, Germany) Measured by diffraction method. The combination of laser diffraction and PIDS technology (Polarization Intensity Differential Scattering Technology) enables measurement of samples with a wide distribution including particles in the size range of 40 nm to 2,000 μm. The principle of the PIDS technique is to illuminate the sample to be tested with horizontally and vertically polarized light having different wavelengths. The intensity of the scattered light at six different angles is then analyzed ((Muller RH, Schuhmann R. Teilchengroβenmessung in der Laborpraxis [Particle size measurement in laboratory practice]): Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart; 1996, Chapter 4, 55-99; Keck CM, Muller RH. Size analysis of submicron particles by laser diffractometry-90% of published measurements are incorrect, Int J Pharm 2008; 355: 150-163; Xu R., Improvements in particle size analysis using light scattering: Muller RH, Mehnert W. (ed), characterizing particles and surfaces Particle and Surface Characterizing Methods: Scientific Publishers Stuttgart; 1997, Chapter 3, 27-56.Calculation of particle size distribution from raw data is as follows: Using Mie theory and assuming that the particles are spherical in shape, for the silicone oil emulsion, the actual refractive index for the particles of 1.40 (Wacker Chemie GmbH. Product Information)-Wacker Silicone Oils AK. 2006) was used for this calculation.The above sample to be characterized was diluted with deionized water for measurement. ˜8 measurements were taken over 90 seconds each, and the values from them were then averaged, and the median (D50 value, D50 value, as the measurement parameter related to the volume-based distribution for evaluating the average (arithmetic mean) The median) and D99 values (diameter at 99% overall pass) were used.

The emulsion according to the invention is preferably free of lecithin and / or free of hydrophobic silicic acid.
Endogenous diseases can be nasal diseases, for example caused by immune deficiencies, autoimmune reactions or other undefined causes.
For example, a disease due to an exogenous cause can be a disease caused by infection with, for example, bacteria, fungi or viruses, or allergens such as dust or pollen.
Mixed forms including endogenous and the endogenous elements are also included therein.
A `` nasal disease '' or `` nasal disease '' refers in particular to rhinitis, in particular rhinitis allergica, viral or bacterial rhinitis or fungal rhinitis (generally infectious) rhinitis, e.g. Rhinitis acuta) or even atopic rhinitis (Rhinitis atrophicans (`` ozaena '')), dry rhinitis (Rhinitis sicca), hypertrophic rhinitis (Rhinitis hypertrophica), vasomotor rhinitis (Rhinitis vasomotorica), pseudomembranous It should be understood to mean rhinitis pseudomembranacea, drug-induced rhinitis, or chronic rhinitis, or two or more of these.
Nasal mucosal diseases also include all (endogenous and intrinsic) rhinitis, such as hay fever.
Intranasal use is required in mammals, particularly humans, especially mammals or humans in need of such treatment.

The preparation of silicone oil emulsions that can be used according to the invention is a method known per se, in particular after adding all the components (optionally also active components), as described, for example, in DE 103 26 188. Or after adding the emulsifier to the aqueous medium in the first stage while being dispersed, followed by homogenization with application of high shear force; or the emulsifier (eg in the case of Span ^™ 80) to the oil phase And in both cases the subsequent combination of the aqueous and oil phases and a geared disperser (e.g. Ultra-Turrax, working with regular stirrers, colloid mills, by sonication or on the rotor-stator principle) (Ultra-Turrax ^TM) T8, Germany, squid Staufen (D-Staufen) - Werke (IKA-Werke) preliminary homogenisation to GmbH & Co KG) by preemulsion (pre-emulsion),及Thereafter, for example, a high-pressure homogenizer, in particular a ring gap homogenizer, for example a micro Love (MicroLab) 40 homogenizer (Germany, Lubeck (D-Lubeck) of APV- Gaulin (APV-Gaulin)) or micro-flu die Heather (Microfluidizer ^TM) (Microfluidics, USA) is pressurized through a narrow ring gap, preferably under a pressure of about 10 to about 140 MPa (100-1,400 bar), and sometimes multiple times, for example 3 times Performed by high pressure homogenization by pressurizing for ~ 10 iterations.
If necessary or necessary for storage stability, the emulsion is then sterilized, such as by autoclaving. A suitable manufacturing process is described in DE 103 26 188 A1. This patent is incorporated herein by reference.
Enrichment with oxygen is optionally carried out as described in EP 2 151 242 A2. The oxygen may be physically obtained, for example, by directly equilibrating gaseous oxygen and an aqueous emulsion of methylpolysiloxane before filling, or by aeration of the solution for use after filling or just before its preparation. Dissolved. For this purpose, a suitably equipped applicator, for example a gas cartridge with an automatic dispensing system built into the drug packaging machine, is suitable.

  During use of a surface-activated dimethicone encapsulated in an airtight container, the oxygen bond may have already been achieved with the oil prior to filling with its appropriate dosage form. . Mixing of 0.5-2% hydrogen peroxide solution or oxygen-storing compounds such as heme protein or perfluorocarbon is possible. However, the preferred drug form is an aqueous emulsion of the dimethicone. Here, oxygen-saturated dimethicone has already been used during the preparation of the emulsion. The first emulsification stage is preferably associated with thorough mixing of the vegetable emulsifier with the oil phase and subsequent incorporation into the aqueous phase, where the application of ultrasound and the increase in temperature are similar. To improve the emulsification. It should be ensured that the emulsification takes place in an oxygen atmosphere. This ensures that maximum physical binding of oxygen to the dimethicone chain occurs. The oxygen content should preferably be at least 2%, calculated on the polysiloxane content of the solution. The maximum bond is achieved at about 7-8% oxygen by weight based on the oil content. Thus, preferably the oxygen-containing emulsion has a bound oxygen content of 1-8, such as 6-8, or especially 7-8% by weight, based on the silicone content. The oxygen bonds in the oil phase are relatively stable and the oxygen is not exchanged with the surrounding emulsion carrier (aqueous medium). The oxygen molecules are specifically enriched and bind associatively to the polysiloxane moiety. Here, the specific bond (which is not intended to be limiting) is probably that the alkyl or methyl residue binds to the valence of each free Si and is also a molecular “ It is achieved in that it forms `` clamps '' because it is strictly arranged so that they have a weakly negatively charged surface on which slightly positively charged oxygen molecules It can be docked or combined.

For example, the oxygenation is preferably carried out at a high pressure, such as about 0.203 to about 1.01 MPa (2 to 10 atm) in a pressure resistant container (e.g. 2 to 40 L or more) in which the emulsion is present, e.g. Oxygen (e.g., introduced over 0.5-2 hours while equilibrating at room temperature, for example, at about 0.253 to about 0.507 MPa (2.5-5 atm) and with stirring and preferably through a frit and stirring. , From a pressure bottle).
The process according to the invention or the method according to the invention for the treatment of a nasal formulation or emulsion of a silicone oil, in particular to be used according to the invention, for mammals, in particular humans, for example as nasal drops or nasally Including intranasal administration as a spray or by inhalation.
Here, possible dosages of the dimethicone solution are generally in at least two parts consisting of 0.1-1 mL, or more frequently applied, for example (e.g. 1-10% by weight) (especially dimethicone) emulsion In the range of 0.1 to 5, especially 0.2 to 2 mL per day, which can contain 0.01 to 5 mg, for example 0.1 to 2 mg of xylometazoline or oxymetazoline in solution.
Similarly, the above formulation for intranasal use may be prepared as an emulsion in a tube (similar to a lotion or as a nasal ointment) or other container, preferably in the form of a nasal drop, for example a bottle with a pipette, or It can be provided in particular as a nasal spray, for example in a spray bottle or other filling unit or as a capsule for an aerosol-forming (microspray) inhaler, for example.
Therefore, the silicone oil emulsions immediately allow the treatment of nasal diseases, which can be used to treat one or more conventional active ingredients with nasal diseases (= nasal, especially nasal mucosal diseases). Further treatment can be included.

Here it is not intended to be a definitive interpretation of the mechanism of action, but without further active ingredients, the action of the silicone oil emulsion is possibly film formation (thin silicone oil base The formation of a protective layer) can contribute to the dispersion (diffusion) of the silicone oil on the nasal mucosa. In conjunction with or separately from this, it is also possible to directly relate, for example, antibacterial effects.
When oxygen is incidentally included, the further improved action of the silicone oil can possibly react with components of the pathogen, on the one hand, on the nasal mucosa and on the other hand the nasal mucosal cells. Although it can contribute to the oxidation of enriched oxygen, which can enhance the defense mechanism of the lysine, it is not intended to be a definitive interpretation.
The improved action of the active ingredient customary for the treatment of nasal diseases is made possible through the silicone oil emulsion used according to the present invention, because the active ingredient is primarily due to its film formation. In addition, direct contact with the nasal mucosa can be maintained for long periods of time, and secondly even when the dosage of the active ingredient is reduced compared to conventional nasal therapeutics containing the active ingredient. However, due to the enrichment of the active ingredients (especially lipophilic) with respect to the silicone oil droplets of the emulsion, they may be supplied to the nasal mucosa, especially in a concentrated form.

Examples of possible active ingredients are:
Anti-inflammatory drugs such as glucocorticoids such as prednisolone, prednisone, methylprednisone, budesonide, flunisolide, fluocortin butyl, fluticasone 17-propionate, mometasone furoate, betamethasone, hydrocortisone,
Aminosalicylate such as sulfasalazine, mesalazine, olsalazine or balsalazide,
Antipyretic,
Antibiotics,
Vasodilators,
enzyme,
antibody,
Secretolytic agents,
Mucopolysaccharide degrading agent,
α-sympathomimetic drugs (especially phenylephrine, ephedrine, tetrizoline, naphazoline, oxymetozoline, xylometazoline or tramazoline), or indanazoline, ethylephrine, phenoxazoline,
Antihistamines such as azelastine, levocabastine, cetirizine, loratidine, terfenadine or fexofenadine;
Leukotriene antagonists such as prankulast, zafirlukast or montelukast;
β ₂ -sympathomimetic drugs;
Mast cell stabilizers such as cromoglycic acid or salts thereof, in particular sodium cromoglycate,
Essential oils,
Or other things,
These pharmaceutically acceptable salts (if a salt-forming group is present) or a combination of two or more of the above active ingredients. Particularly preferred are oxymetazoline and especially xylometazoline.

Salts are the main and most important conventional pharmaceutically available salts, such as acid addition salts (when basic salt-forming groups such as primary, secondary or tertiary amino groups are present); or ( Salts with bases (in the presence of acidic groups such as —COOH or SO ₃ H).
Particularly preferred are α-sympathomimetics, in particular one or more oxymetazolines (very particularly preferred), xylometazolines (very particularly preferred) or naphazolines.
Based on the total formulation, the content of such active ingredients on a mass basis is, for example, about 0.01 to 10% by mass, preferably 0.05 to 4% by mass.
Similarly, the invention also relates to subject matter of the invention as set forth in the claims and abstract, which are hereby incorporated by reference.

The following examples serve to illustrate the invention without limiting the scope of the invention.
Example 1: Production of nasal preparations
Production of oxygen-treated silicone oil emulsion:
20mL of silicone oil M 500 MC (Wacker Chemie (Wacker Chemie) GmbH) and 500mL of Poloxamer (Poloxamer) 188 (Lutrol (Lutrol ^TM), Germany, Ludwigshafen BASF (BASF) Inc.), Ultra-Turrax ( Ultraturrax ^TM ) Add dropwise to 75 mL of distilled water in 4x, homogenize roughly for 5 minutes at stage 8, and then process in a high pressure homogenizer to a stable silicone oil emulsion ready for use (Yonekura K , Hayakawa K, Kawaguchi M, Kato T, Preparation of stable silicone oil emulsions in the presence of hydroxypropyl methyl cellulose, Langmuir, 1998; 14: 3145-3148 ). After 1 hour storage and quality control (droplet size, surface activity), the emulsion is introduced into a sterile 100 mL glass bottle with a screw-in closure with a 5 cm long PE plastic capillary (5 mm ID) And hermetically seal. Capillary is a PTE hoses, Konokishia having a pressure reducing valve (Conoxia ^TM) pressure bottle is attached to (Germany, Prague (Pullach, Linde (Linde) AG of Germany)), also at room temperature, about Aerated at 0.405 MPa (4 atm) for 60 minutes. During the venting, a small volume of the upper gas dome is discharged 2-3 times through the screw-in closure to remove as much as possible any extraneous gas mixture still present from the silicone oil. Accordingly, the oxygen-treated silicone oil emulsion is ready for further use.

Preparation of oxymetazoline or xylometazoline stock solutions:
500 mg of oxymetazoline or xylometazoline (Sigma-Aldrich, Munich, Germany) puriss is dissolved in 250 mL of distilled water and warmed gently and vigorously. While stirring, fill into sterile 25 mL glass bottle and hermetically seal. Store these bottles at 4 ° C. until use.
Manufacture of rhinitis drug A for application in:
Pipette 5 mL of the above oxygenated silicone oil solution and 0.25 mL of the above OX / XTZ stock solution into a 10 mL nasal application unit (drip bottle or spray bottle), and also add 4.75 mL of 1.8% NaCl solution to the specified volume. Replenish until. After the phases are vigorously shaken and mixed, the application unit is hermetically sealed and released for use.
Production of rhinitis drug B for application in:
100 mL of Dimethicone SE 2 MC (Wacker Chemie AG, Munich, Germany) is filled into a glass pressure bottle as described above and aerated with oxygen by the method described above. These are processed in the same manner as described above to obtain a rhinitis therapeutic agent.

Example 2: Use in patients As an example, the formulation from Example 1 was used in patients as follows:
After external washing of the nose, the rhinitis therapeutic agent is introduced into each nasal cavity as quickly as possible by pushing the nose wings of the nose with two fingers together as quickly as possible with an applicator unit (drop dispenser or pressure spray) Do (2-3 spray stroke or 3-4 drops). After 10-15 seconds, the application is complete. If necessary, this is repeated until the discharge of the secretion is permanently terminated.
The meaning is as follows:
SE-2: Silicone oil emulsion base = Dimethicone SE 2 MC (Wacker Chemie GmbH) (Rhinitis Treatment B);
XMZ = xylometazoline;
OX = oxymetazoline.
Data expressed in mg / mL are based on the final concentration of OX or XMZ in the rhinitis drug.
(A) The following patients with various forms of rhinitis were treated with oxygen-saturated SE 2 emulsion.
Patient 1 : JO, 39 years old, female
Diagnosis : Acute influenza infection with rhinitis, chronic rhinitis with potential dependence:
Aqueous mucus drainage at 4-5mL / hour on the first day
Application :
First day of treatment : 2 spray strokes SE-2 / 0.5mg / mL every 4 hours + 3 spray strokes OX before going to bed
Treatment Day 2 : 2 spray strokes every 6-7 hours
Day 3 of treatment : 2 spray strokes every 12 hours
Day 4 of treatment : 2 more spray strokes in the morning
Day 5 : No viscous suppurative secretions or other occur, no symptoms.
Self-assessment based on 10-year long-term use of 0.8-1mg / mL OX aqueous nasal spray:
No rapid healing without any residue, no nasal sinus, no inflammation of the nasal opening (semi-infectious rhinotracheitis).
The patient will use the SE-2 emulsion repeatedly in the case of rhinitis.

Patient 2 : JN, 23 years old, male
Diagnosis : Rhinitis vasomotorica (allergy to hop protein), large amount of watery nasal discharge (2-3 pacers handkerchief) for 10-20 minutes after ingestion of the allergen
Start with 0.5 mg / mL SE-2 emulsion + OX / seawater every hour; noticeable decrease in the watery secretion within 2-3 hours, use 3 times every 12 hours, typical for rhinitis Complete remission without mucosal redness and swelling, no vascular obstruction, no sinus obstruction.
Self-assessment : A complete and rapid offset of the rhinitis allergy will immediately re-use SE-2 NT. “Pleasant drug”.
Patient 3 : PL, 37 years old, male
Diagnosis : Chronic rhinitis, at least 3 episodes per month, mixed rhinitis viral allergy, NT: OX / seawater drugs, nasal oil, nasal cream forced use
Treatment with SE-2 OX emulsion for 4 months :
First 2 months: combination with 0.5 mg / mL OX-seawater; last 2 months: SE-2 and 0.25 mg / mL OX-seawater, generally once every 8 hours for the last month Spray causes only 2 episodes of subacute rhinitis, markedly shortened episode of disease: duration of up to 2 days.
Self-assessment : Very good efficacy with unprecedented incidence of rhinitis, clearly superior to standard commercial OTC products.
Patient 4 : EN, 71 years old, female
Diagnosis : Severe acute rhinitis with subchronic tracheobronchitis Day 1: Immediately within 7-8 hours, severe suppurative-watery nasal mucus discharge, trigeminal neuralgia with sinus disorders Severe left side headache, commercial nasal sprays and nasal drops have no effect.
2nd to 4th days: First start with application of SE-2 / OX saline nasal spray, used every 3 hours, then after 12 hours, apply only 2 times / day, significantly reduced Rapid healing of spray stroke volume and associated signs of inflammation.
Self-evaluation : very good efficacy, firstly a “significant” healing tendency.

Patient 5 : HR, 42 years old, male
Diagnosis : Acute rhinitis with viral infection (Rhinitis acuta); first “nasal obstruction” due to mucosal swelling on the first day, sudden watery nasal discharge with up to 10 crushing attacks per hour .
Beginning with 3 spray strokes, 3 times each, and during the first hour at each time point, SE-2 / 0.5 mg / mL XMZ, then remission of the acute secretion phase over the next 4 hours.
Further introduction of SE-2 / 0.5 mg / mL XMZ, followed by nasal drops, is still required only 3 times per 16 hours, and heals after 4 days without further olfactory disturbance.
Self-assessment : good efficacy with reduced fluid nasal mucus secretion still present in the early days, however it stopped after 4 hours of first spray application.
Patient 6 : CL, 6 years old, male
Diagnosis : Chronic rhinitis with onset of chills with frequent fever:
For the first symptom, immediate use and application of SE-2 / 0.125mg / mL XMZ in seawater (1 spray stroke in each nostril at morning, noon and evening).
Results : No rhinitis, no mucosal redness in the nasal-pharyngeal cavity, no pain.
Parental assessment : Complete prevention of rhinitis, no other rhinitis spray suitable for children, such results have never been seen before and will be used again in the next infection.
Patient 7 : SN, 44 years old, female
Diagnosis : Allergic vasomotor rhinitis when exposed to pollen, with common symptoms such as headache, subthermic body temperature and joint problems.
After severe mucosal swelling in the nose and pressure in the sinuses, it begins with suppurative mucinous rhinitis and “nasal pain” and increases markedly. Use SE-2 / 0.25 XMZ several times during the day and 2-3 times at night. The reason is the dryness of the mouth and the impossibility of breathing through the nose.
After 3 days, the need for spray application was significantly reduced (2 times / day) and healed after 5 days.
Self-assessment : rapid decrease in allergic episodes above, otherwise lasting 7-10 days, very good effect.

Patient 8 : CS, 69 years old, female
Diagnosis : An almost permanent catarrhic condition with an immunodeficiency syndrome with chronic rhinitis disorder, dryness of the nose and mucus nasal discharge.
Use SE-2 / 0.25mg / mL XMZ twice during the day and once before going to bed in the evening.
No rhinitis attack, no misunderstanding, rapid nasal “curing”; 14-day application, no symptoms for 4-6 weeks thereafter.
Self-evaluation : very good effect, comfortable “soft” spray performance, will use this over and over again.
Example 3: Oxygenated and non-oxygenated dimethicone emulsion-antibacterial effect on pharyngeal cells :
Abbreviation: DIM: Dimethicone emulsion;
OxiDIM: oxygenated dimethicone emulsion;
HEp2 cells: human epithelial cell line derived from the pharynx (epithelioma)
In the study on the effect of dilute OxiDIM emulsions with various dimethicone chain lengths on the adhesion and internalization of E. coli to HEp-2 cells, 3% DIM emulsions were also studied. The most striking finding here was that these DIM dilutions still showed very low internalization suppression, with no exceptions, even at only 1: 3,000.

Experimental procedure : HEp-2 cells were incubated in 12 25 mL cell culture bottles each until a complete cell layer, and then during the cell culture medium change, 5,000 E. coli in 10 mL medium was B2332 (derived from cryogenic culture, supplied by the Institute of Medicinal Microbiology, University Clinic Jena) as its control and Conoxia (O2 (+ In each case, pre-equilibrated with)) or without aeration (-), it was added to 5 dilution steps of the 3% dimethicone emulsion (M500). After 24 hours of incubation, the cell layer was rinsed with cell culture medium. Next, dead Hep-2 cells in 4 quadrants were counted on an inverted microscope by vital staining. Two tests were performed in the same manner using 3% dimethicone emulsions M1000 and M2000.
These results are summarized in the following table: For equalization with respect to% internalization, a marked and stronger inhibition of internalization can be seen for the oxygenated dimethicone emulsion. The optimal chain length of the dimethicone should be determined to be in the range of M 1000-2000.
Table: Inhibition of E. coli (B2332) internalization into Hep 2 cells by 3% dimethicone solutions with different chain lengths (M ...) with or without oxygen:

括弧内の値：オイル成分無しのコントロール = 各研究において100％(M 500、M 1000又はM 2000)

Values in parentheses: control without oil component = 100% in each study (M 500, M 1000 or M 2000)

Values that are found to have stronger inhibition compared to those without oxygen treatment are highlighted by underlining.
For example, at a dilution of 1: 3000, the 77% inhibition found in relation to M 2000-OxiDIM is a DIM emulsion (maximum inhibition: 3% M 2000 DIM emulsion, 54% at a dilution of 1: 2000) Was not found in any experiment on.
Result: DIM emulsion without oxygen treatment has a significantly weaker antibacterial effect than OxiDIM emulsion.
Example 4: Study on Efficacy in Human Patients Using the following research plan, clinically the use of an oxygen-enriched silicone oil-containing xylometazoline-weight loss formulation (Group 3) for application to the nose Identify the advantages over the standard 0.1% xylometazoline formulation and the superiority of the oxygen-enriched silicone oil-containing formulation over the non-oxygen-enriched silicone oil-containing formulation:

Plan: Study controlled and randomized groups of the same trend according to GCP.
Group and group size:
4 groups: 25 participants each:
1. Silicone oil;
2. Silicone oil + oxygen;
3. Silicone oil + oxygen + 0.01% xylometazoline;
4. Standard dose of 0.1% xylometazoline.
Inclusion criteria / indication:
Acute rhinitis exclusion criteria:
Drug-induced rhinitis Serious latent disease measurement parameters:
Nasal peak flow
Number of handkerchiefs used Symptom improvement points
Targets achieved on day 0, 3, 7, 10:
Significant reduction in disease duration;
Significant improvement in the symptoms with non-inferiority related to physical parameters;
Safety parameters:
Complete blood count and sedimentation at the start and end points.

Example 5: Use of Oxygenated Silicone Oil Emulsion 2 MC 0.5 + “Seawater” Salt Solution 0.5 for the Prevention of Acute Viral Rhinitis
In October 2014, two participants (JN male, 23-year-old and MS male, 24-year-old) out of a group of 5 students who completed a 12-hour overseas trip had their Application by spraying nasal spray without active ingredient after 4 and 8 hours (3 spray strokes in each nostril at each time point) was utilized. These two spray users showed no symptoms of acute or allergic rhinitis after the end of the flight and in the following days. The other three participants of the travel group suffered from mild influenza infection, subfever temperature (37.3-37.8 ° C) and acute rhinitis within 24 hours. All participants used this nasal spray formulation on their return flight after 3 weeks, after which none of the participants showed symptoms of acute rhinitis.

Claims (13)

  A silicone oil-containing formulation for nasal application for use in an intranasal treatment of a disease caused by an intrinsic nasal disease and / or an exogenous cause.   2. The silicone oil-containing formulation according to claim 1, wherein the nasal disease is caused by bacteria, fungi, viruses and / or allergens.   If the nasal disease is rhinitis, especially allergic rhinitis, infectious rhinitis, atrophic rhinitis, dry rhinitis, hypertrophic rhinitis, vasomotor rhinitis, pseudomembranous rhinitis, drug-induced rhinitis, or chronic rhinitis, or these The silicone oil-containing formulation according to claim 1, which should be understood as representing two or more.   The silicone oil-containing preparation according to claim 1, 2 or 3, wherein the silicone oil or the preparation is enriched with oxygen.   The silicone oil-containing preparation according to any one of claims 1 to 4, which is in the form of an emulsion of silicone oil in an aqueous medium.   6. An oil-in-water emulsion according to any one of claims 1 to 5 in the form of an oil-in-water emulsion containing a polydialkylsilane liquid at room temperature in the presence of an ionogenic or non-ionogenic emulsifier in an aqueous medium. Silicone oil-containing preparation. The polydialkylsilane has a kinematic viscosity in the range of 10 to 5,000 mm ² s ^-1 and the emulsifier is an ionogenic emulsifier such as sodium dodecyl sulfate, or preferably a non-ionogenic emulsifier such as Low molecular weight non-ionogenic emulsifiers or block copolymers such as macrogol glycerol ricinoleate;
Polyoxyethylene sorbitan fatty acid ester,
A mixture of sorbitol and its partial fatty acid ester and oleic acid;
Block copolymers having phospholipid ethylene oxide and propylene oxide units;
Hydroxypropylmethylcellulose;
One form of silicone surfactant in the form of a copolymer of polydimethylsilane and organic glycol or obtained by methanol fractionation;
Sucrose ester;
Or a mixture of two or more of these,
Or similarly granular solids, such as modified silicon dioxide particles,
Block copolymers having in particular ethylene oxide and propylene oxide units, or even sucrose units containing stearic acid as the predominant acyl content,
Polyoxyethylene sorbitan fatty acid ester, alone or mixed with a mixture of partial fatty acid ester of sorbitol and its anhydride and oleic acid,
Macrogol glycerol ricinoleate and phospholipids,
Or a mixture of two or more of these,
The silicone oil-containing preparation according to claim 6, which is selected from the group comprising   8. The aqueous medium according to any one of claims 1 to 7, characterized in that the formulation contains pure water, buffer solution or salt solution or sea water with or without further additives. Silicone oil-containing preparation. Furthermore, preferably an anti-inflammatory agent such as glucocorticoid, such as prednisolone, prednisone, methylprednisone, budesonide, flunisolide, fluocortin butyl, fluticasone 17-propionate, mometasone furoate, betamethasone, hydrocortisone, aminosalicylate such as sulfasalazine, Mesalazine, olsalazine or balsalazide,
Antipyretic,
Antibiotics,
Vasodilators,
enzyme,
antibody,
Secretion decomposing agent,
Mucopolysaccharide degrading agent,
α-sympathomimetic drugs, especially phenylephrine, ephedrine, tetrizoline, naphazoline, oxymethazoline, xylometazoline or tramazoline, or indanazoline, ethylephrine, phenoxazoline,
Antihistamines such as azelastine, levocabastine, cetirizine, loratidine, terfenadine or fexofenadine;
Leukotriene antagonists such as plancrust, zafirlukast or montelukast;
β ₂ -sympathomimetic drugs;
Mast cell stabilizers such as cromoglycic acid or salts thereof, in particular sodium cromoglycate,
Essential oils,
A pharmaceutically acceptable salt thereof, or at least one active ingredient selected from a combination of two or more of the above active ingredients, which also contains an active ingredient for treating nasal diseases. The silicone oil-containing preparation according to any one of the above.   Furthermore, the silicone oil containing formulation of any one of Claims 1-9 which also contains oxymetazoline or especially xylometazoline.   11. A silicone oil-containing formulation according to any one of claims 1 to 10, which can be produced by use of a high-pressure homogenization stage and optionally in particular by introduction of oxygen.   12. The silicone oil-containing preparation according to any one of claims 1 to 11, relating to nasal intrinsic diseases and / or exogenous causes, for example diseases caused by bacteria, fungi, viruses or allergens, in particular nasal mucosa Rhinitis, especially rhinitis, above all allergic rhinitis, infectious rhinitis, atrophic rhinitis, dry rhinitis, hypertrophic rhinitis, vasomotor rhinitis, pseudomembranous rhinitis, drug-induced rhinitis or chronic rhinitis, or these Use for the manufacture of a pharmaceutical formulation for intranasal application for the purpose of treating two or more.   A process or method for treating a disease of the nose, especially the nasal mucosa, especially for mammals, especially humans, in need of such treatment, in an amount effective for the disease of the nose. Item 12. The process or method comprising a nasal administration of the silicone oil-containing preparation according to any one of Items 1 to 11.